Control of selective estrogen receptor modulators

ABSTRACT

The treatment of an estrogen sensitive condition by the administration of a selective estrogen receptor modulator is improved by additionally administering a progestationally active compound to the recipient. The additional agent can express both progestational and androgenic activity or an androgenically active material can be employed, if desired. Additionally, clomiphene in an array of isomeric ratios (EN:ZU) can be used alone for prevention of osteoporosis, maintenance of a healthful blood lipid profile, and prevention of breast tumors, or to sustain amenorrhea.

This is a continuation-in-part of application Ser. No. 08/888,183, filedJul. 3, 1997 now abandoned.

BACKGROUND OF THE INVENTION

The use of estrogens in the course of treatment of a variety ofconditions is well known. For example, the most prevalent form of oralcontraception is the so-called combined oral contraceptive preparation,a pill that combines both estrogen and a progestin. Apparently, theprogestin acts foremostly to block gonadotropin release while theestrogen component primarily provides endometrial control to diminishbreakthrough bleeding. Another well-known use is long term estrogenreplacement therapy which is common for post-menopausal and otherestrogen deficient women. Other estrogen dependent conditions includeendometriosis, uterine fibroid tumors (leiomyomata), pre-menstrualsyndrome, dysfunctional uterine bleeding, breast tumors (benign andmalignant) and the like.

Despite their value, estrogen treatments are also associated withundesirable side effects. For example, estrogen therapy has beenassociated with an increased incidence of endometrial cancer, especiallydue to the continual “unopposed” estrogen-induced proliferation of theendometrium. Other side effects include uterine bleeding andcyclotherapeutic withdrawal menstrual bleeding during a time in theirlives when many women welcome cessation of menstrual bleeding as anormal occurrence in menopause. Estrogen therapy has also beenimplicated in the development of a variety of disorders includinggallbladder disease, hypertension, abnormal glucose tolerance,hypercoagulable states and breast cancer, although some of theseobservations are antidotal in nature and have not been confirmed.

There have been numerous efforts to counteract the ill effects ofestrogen therapy. For instance, attempts have been made to coupleestrogen therapy with short periods of anti-estrogen supplementation.Another approach is to use anti-estrogens in place of the estrogen.Certain compounds are known as “anti-estrogens” because they can bind tothe estrogen receptors and competitively block the binding of the morepotent estrogens such as estradiol. Among the best known of theseanti-estrogens are clomiphene and tamoxifen. However, all suchanti-estrogens can be, in fact, active estrogens depending on thetissue, dose/regimen and hormonal milieu of the drug exposure. These aremixed function agonistic/antagonistic activities. The degree to whichthe anti-estrogen acts as an estrogen also depends on the particularmaterial and the tissue site.

While anti-estrogen therapy has been successful, it is not without itsown problems. As is know, there is a hypothalamic-pituitary-gonadal axisinvolved in endogenous hormone production. As estrogen binds to itsreceptors, there is a feedback mechanism which regulates the endogenousproduction of pituitary gonadotropins and, in turn, estrogen so that thehormonal milieu remains within the physiological range. When ananti-estrogen binds to the estrogen receptors, altered estrogen feedbackmechanisms are implicated in a pharmacological manner compared to whenestrogen binds normally. The anti-estrogens themselves can inducemultiple follicular growth which, in turn, causes the production ofendogenous ovarian estrogens. A favorable example is the use ofclomiphene for ovulation induction. For the first anti-estrogen doseadministration and continuing for some period of time, the endogenousestrogen produced as a consequence of the multiple follicular growth maynot appear to pose a problem. However, at some point, which is totallyunpredictable and which varies from individual to individual, endogenousestrogen can be produced such that the quantity of estrogen present canelevate blood levels well above 300 pg/ml. Indeed, estradiolconcentration in plasma may exceed a few thousand in some instances.Therefore, while the use of an anti-estrogen seeks to reduce or modifyor eliminate the side effects of estrogen, its use over time may havethe reverse effect by inducing an excess concentration of estrogen. Notonly may the use of the anti-estrogen exaggerate the estrogen sideeffects which it seeks to avoid, but the anti-estrogen may also eveneliminate the primary benefit of the administration in the firstinstance. For example, a “run away” endogenous estrogen can induceovulation in those situations where the administration of theanti-estrogen was designed to provide contraception. This feature ofanti-estrogen therapy makes the establishment and maintenance ofappropriate dosages of anti-estrogen difficult and in some casesimpossible, especially when the therapeutic goal is simultaneous tolimit excessive estrogenic impact in one tissue, while itself providingadequate estrogenic stimulation in another tissue.

It is therefore the object of the present invention to keep thehypothalamus and pituitary from becoming deranged and thereby preventmultiple follicular growth and the endogenous estrogen sustained,supraphysiological elevations which result from ovarianhyperstimulation. This and other objects of the invention will becomeapparent to those of ordinary skill in the art from the followingdetailed description.

SUMMARY OF THE INVENTION

This invention relates to a method of using a SERM such as clomiphene,for instance, pre- and postmenopausally, e.g., in hormone replacementtherapy to prevent osteoporosis, cardiovascular disease and breastcancer, as well as preventing the hypothalamus and pituitary fromoperating in a deranged manner during any SERM therapy. Moreparticularly, the invention involves superposing upon the use of aselective estrogen receptor modulator, the co-administration of acompound progestationally active to women, either of reproductive agewomen who are pre-menopausal or who are post-menopausal. Theprogestationally active compound may also exhibit androgenic activity oran androgenically active compound can be coadmistered.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, an additional hormonal therapyis superposed upon the use of a selective estrogen receptor modulator(also known as a SERM, selective estrogen or anti-estrogen) in the knownuse of the SERM, for instance, as in treating or controlling an estrogensensitive condition. Estrogen sensitive conditions include, but are notlimited to, contraception, hormone replacement therapy, endometriosis,leiomyoma, dysfunctional uterine bleeding, premenstrual syndrome,hormonal dependent cancers, such as those of the breast, endometrial andovarian, and the like. Some SERMs have been indicated for the preventionof post-menopausal osteoporosis, modulation of serum lipid profiles andbreast cancer prevention.

Any known SERM can be used in the practice of this invention for itsknown utility in the treatment or modification of a medical condition inmammals. Examples of known SERMs include, but are not limited to,clomiphene; cycladiene; tamoxifen; nafoxidine; nitromifene citrate(N-55,945-27); 13-ethyl-17α-ethynl-17β-hydroxygona-4-9-11-trien-3-one(R2323); diphenol hydrochrysene; erythro-MEA; allenolic acid;cyclofenyl; chlorotrianisene; ethamoxytriphetol; triparanol; CI-626;CI-680; MER-25; U-11,555A; U-11,100A; ICI-46,669; ICI-46,474; CN-55,945;compounds of the formula:

where R₁ is hydrogen, an aromatic group or alkyl of preferably no morethan nine carbon atoms, R is an aromatic or alkyl group of preferably nomore than nine carbon atoms and various of their derivatives; thetriphenyl compounds described in U.S. Pat. No. 2,914,563 which are ofthe formula:

wherein one of the R groups is a basic ether of the formulaOC_(n)H_(2n)A in which n is 2, 3 or 4 and A is a C₁₋₄ dialkylaminogroup, N-piperidyl or β-morpholinyl and the other R and R₁ are hydrogen,halogen or methoxy while X is halogen; as well as benzothiophenes suchas those described in U.S. Pat. No. 5,624,940 of the formula:

in which R¹ and R³ are independently hydrogen, C¹⁻⁴ alkyl,—CO(C₁₋₆alkyl) or —COAr in which Ar is optionally substituted phenyl, R²is pyrrolidino, hexamethyleneamino or piperidino, or a salt thereof.Example of the benzothiophenes include raloxifene(6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinethoxy)-benzoyl]benzo[b]thiophene)and LY353381.HCl benzothyphenes. The SERMs can also be employed in theform of their pharmaceutical acceptable non-toxic salt or complexes.Examples include the acid addition salt such as, for instance, citrate,hydrochloride, hydrobromide, sulfate, phosphate, nitrate, oxalate,fumarate, gluconate, tannate, maleate, acetate, benzoate, succinate,alginate, malate, ascorbate, tartrate and the like. The complexes can bewith metals or various organic moieties.

The SERM aspect of the present invention is similar to the previous useof such materials for the treatment of estrogen dependent or othermedical conditions. Thus, not only may any known SERM be employed, butalso the dosage amount and mode of administration heretofore employedcan also be employed in the practice of the present invention. ThoseSERMs which have an asymmetric atom can be used as the racemate or inany of the chiral or entomeric forms or mixture of such forms. Forexample, clomiphene can be used with an array of isomeric ratios(EN:ZU), as well as employing only one of the isomers. Thus, the routeof administration can be in any conventional route where the SERM isactive, for instance orally, intravenously, subcutaneously,intramuscularly, sublingually, percutaneously, rectally, intranasally orintravaginally. Similarly, the administration form can be a tablet,dragee, capsule, pill, nasal mist, aerosol, pellet, implant (or otherdepot) and the like.

Superposed on the SERM administration is the use of a progestationallyactive compound, optionally with androgenic activity or in combinationwith an androgenically active compound. The additional agent can beprogesterone, a synthetic progestin analog or even an anti-progestinhaving agonistic activity (i.e., progestin-like activity without relyingon its “non-competitive anti-estrogenic” properties). Examples ofprogestins which can be utilized include progesterone,medroxyprogesterone acetate, norgesterel, levo-norgesterol,norethindrone and its esters, norethynodrel, ethynodiol diacetate,chlormadione acetate, cyproterone and its esters, norethindrone,gestodene, desogestrel, norgestimate, and the like. Examples ofandrogenic compounds include low doses of testosterone, androsteridioneand DHT. Some compounds such as danazol and levonorgestrel exhibit bothandrogenic and progestogenic activity simultaneously.

The antiprogestin can be a progesterone receptor antagonist or anypharmaceutically suitable agent that counteracts the normal biologicalactivity of progesterone. A preferred antiprogestin is a progesteronereceptor antagonist. For example, RU 486 is particularly suitable in thepractice of this invention.

Examples of antiprogestins which can be employed in this invention areRU 486 (“mifepristone”, Roussel Uclaf, Paris; U.S. Pat. No. 4,386,085);and the steroids described in the following patents and patentapplications: U.S. Pat. No. 4,609,651, especially the compoundlilopristone(11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(3-hydroxy-prop-1-(Z)-enzyl-4,9(10)estradien-3-one); U.S. application Ser. No. 06/827,050, especially thecompounds11β-(4-acetylphenyl)-17-hydroxy-17α-(1-propenyl)-4,9-estradien-3-one and11β-(4-acetylphenyl)-17β-hydroxy-17α-(3-hydroxy-1(2)-propenyl)-4,9-estradien-3-one;U.S. application Ser. No. 07/283,632; U.S. Pat. No. 5,095,129; and otheranti-gestations, e.g., U.S. Pat. No. 4,891,368.

Other examples of progestinally active compounds are well known in theart.

The amount of progestationally and optional androgenically activecompound which is administered is that which is effective to regulateendogenous estrogen secretions to a desired level. Thereby, ovulationcan be blocked and endometrial growth and menstruation can becontrolled. As a general proposition, the blood estrogen (endogenous)concentration achieved can be in the range of about 25 to 125 pg/ml andmore preferable about 60 to 90 pg/ml, although other values can beselected if desired.

The progestinally and optional androgenically active compound can beadministered by way of any art recognized means as practiced in thepharmaceutical arts. For example, it can be formulated in combinationwith the SERM or separately so that it is administered orally,subcutaneously, intramuscularly, buccally, by a skin patch fortransdermal absorption, contained within an inert matrix which isimplanted within the body and in the depot state or intravaginally in amatrix that releases the material.

Formulations containing the SERM or the progestationally active andoptional androgenically active compound, together with a suitablecarrier, can be a solid dosage form which includes tablets, capsules,cachets, pellets, pills, powders and granules; topical dosage formswhich include solutions, powders, fluid emulsions, fluid suspensions,semi-solids, ointments, pastes, creams, gels or jellies and foams; andparential dosages forms which include solutions, suspensions, emulsionsor dry powder. The composition can in addition contain a pharmaceuticalacceptable diluents, fillers, disintegrates, binders, lubricants,surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers,buffers, humeticants, moisturizers, solubilizers, preservatives andother means of augmenting the medicinal entity. The means and methods ofadministration are known in the art and the artisan can refer to variouspharmalogic references for guidance. One such reference is “ModernPharmaceuticals”, Banker & Rhodes, Marcel Dekker, Inc. 1979 and anotheris Goodman & Gilman's, “The Pharmaceutical basis of therapeutics”, 6thEd., MacMillan Publishing Co., New York, 1980.

If desired, the two (or three) components, namely the SERM and theprogestationally active and optional androgenically active compound, canbe coadministered utilizing the same or different dosage forms or means,for example for the same tablet. Application of the components,compositions and the methods of this invention for the medical and/orpharmaceutical use which are described in this text can thus beaccomplished by any clinical, medical or pharmaceutical methods ortechniques as are presently or prospectively known to those skilled inthe art.

The administration of the components can be either periodic such as aweekly basis or continuous, that is on a daily administration. Dailyadministration is preferred because individuals are more likely tofollow the treatment regimen and not to forget or overlook a periodicadministration schedule. Amounts can be lowered or raised based on theadministration regimen and based on the characteristics of theindividual receiving the treatment. Variations of dosage based or theroute of administration may vary and such changes can be determinedpracticing known techniques.

The pharmaceutical formulations can be provided in kit form containing aplurality of dosage units intended for ingestion on successive days.Preferably, the plurality is in multiples of seven.

In order to further illustrate the present invention, specific examplesare set forth below. It would be appreciated, however, that theseexamples are illustrative only and are not intended to limit the scopeof the invention.

EXAMPLES

1. Clomiphene is used alone at 100 mg/day for the treatment ofendometriosis. After 15 days, the serum estrogen reached 500 pg/ml.Levonorgestrel at 75 mcg/day is then also administered. The serumestrogen retreated to physiological value.

2. Raloxifene at 500 mg/day and medroxprogesterone acetate at 12 mg/daywere administrated to treat leiomyoma. Serum estrogen remained atphysiological levels.

3. Example 1 is repeated using clomiphene EN:ZU isomers in a ratio of8:1.

4. Clomiphene ZU isomer at 50 mg/day and norgestimate at 100 mcg/day arecoadministered while the serum estrogen remained at physiologicallevels.

5. Clomiphene is used alone at 100 mg/day for the treatment ofendometriosis. After 15 days, the serum estrogen reached 500 pg/ml.Danazol at 100 to 800 mg/day is then also administered. The serumestrogen retreated to physiological value.

6. Example 5 is repeated using testosterone at a dosage of 2 to 10mg/day in place of the danazol.

What is claimed is:
 1. In the method of preventing hormonal dependentbreast, cancer in a host by administering an effective amount of aselective estrogen receptor modulator to the host, the improvement whichcomprises additionally administering an agent which exhibitsprogestogenic activity to the host in an amount effective to modulatethe side effects of the selective estrogen receptor modulator.
 2. Themethod of claim 1 wherein the selective estrogen receptor modulator isclomiphene.
 3. The method of claim 1 wherein the selective estrogenreceptor modulator is a benzothiophene.
 4. The method of claim 1 whereinthe agent which exhibits progestogenic activity is an antiprogestin. 5.The method of claim 4 wherein the antiprogestin is a progesteronereceptor antagonist.
 6. The method of claim 5 wherein the selectiveestrogen receptor modulator is clomiphene.
 7. The method of claim 5wherein the selective estrogen receptor modulator is a benzothiophene.8. The method of claim 4 wherein the amount of antiprogestin is thatsufficient to maintain the blood estrogen concentration in the range ofabout 25 to 125 pg/ml.
 9. The method of claim 8 wherein the amount ofantiprogestin is that sufficient to maintain the blood estrogenconcentration in the range of about 60 to 90 pg/ml.
 10. The method ofclaim 1 wherein the agent which exhibits progestogenic activityexpresses both androgenic and progestogenic activity.
 11. The method ofclaim 10 wherein the agent which exhibits progestogenic activitycomprises combination of an androgen and a progestin.
 12. The method ofclaim 10 wherein the agent which exhibits progestogenic activity is asingle material which expresses both activities.
 13. The method of claim12 wherein the agent which exhibits progestogenic activity is danazol orlevonorgestrel.
 14. A kit comprising a plurality of tablets containingan amount of a selective estrogen receptor modulator effective toprevent hormonal dependent breast, cancer and an agent which exhibitsprogestogenic activity in an amount effective to modulate the sideeffects of the selective estrogen receptor modulator.
 15. The kit ofclaim 14 wherein the selective estrogen receptor modulator is clomipheneor a benzothiophene.
 16. The kit of claim 14 wherein the agent whichexhibits progestogenic activity is an antiprogestin.
 17. The kit ofclaim 16 wherein the antiprogestin is a progesterone receptorantagonist.
 18. The kit of claim 14 wherein the agent expresses bothandrogenic and progestogenic activity.
 19. The kit of claim 18 whereinthe agent comprises the combination of an androgen and a progestin. 20.The kit of claim 18 wherein the agent is a single material whichexpresses both activities.
 21. The method of claim 1, wherein the hostis a pre-menopausal woman.
 22. The method of claim 1, wherein the hostis a post-menopausal woman.